The long-range goal of the proposed research is to determine the molecular nature of the current-carrying mechanisms in the membranes of excitable cells by studying the variations that occur in the electrical properties of these membranes when the genes that code for these properties are manipulated. The first three years of this project will be limited to electrophysiological studies of the somal membranes of ganglion nerve cells of snails. The research will be divided into two phases: (1) The biophysical properties of the membrane currents found in these cells will be examined, using a single macroelectrode voltage clamp that allows internal dialysis of the neuron. The voltage dependencies, kinetics and sensitivity to intracellular calcium and hydrogen ions will be measured for each of the membrane currents, but the Ca channel will be studied in greatest detail. The selectivity and blocking of divalent cations of the snail Ca channel will be completely characterized, and its kinetics and instantaneous current-voltage relations will be studied. (2) The variations in membrane properties that exist between neurons will be analyzed. The extent and types of variation will be measured between species and between classes of neurons in one species. An environmentally controlled component of this variation will be looked for in neurons from snails acclimated to different temperatures, and genetically determined variation will be sought between isogenic strains of the snail Helisoma. Not only will this research provide a more precise understanding of a number of currents which are generally present in nerve, muscle and secretory cells, but it will also lay the foundation and develop techniques for studying the genetic control of electrical properties of membranes in animals where genetic studies are conveniently done.